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Multiple Myeloma, Gammopathies

Genetic deletion of Sost or pharmacological inhibition of sclerostin prevent multiple myeloma-induced bone disease without affecting tumor growth

Leukemia volume 31, pages 2686–2694 (2017)Cite this article

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Abstract

Multiple myeloma (MM) causes lytic bone lesions due to increased bone resorption and concomitant marked suppression of bone formation. Sclerostin (Scl), an osteocyte-derived inhibitor of Wnt/β-catenin signaling, is elevated in MM patient sera and increased in osteocytes in MM-bearing mice. We show here that genetic deletion of Sost, the gene encoding Scl, prevented MM-induced bone disease in an immune-deficient mouse model of early MM, and that administration of anti-Scl antibody (Scl-Ab) increased bone mass and decreases osteolysis in immune-competent mice with established MM. Sost/Scl inhibition increased osteoblast numbers, stimulated new bone formation and decreased osteoclast number in MM-colonized bone. Further, Sost/Scl inhibition did not affect tumor growth in vivo or anti-myeloma drug efficacy in vitro. These results identify the osteocyte as a major contributor to the deleterious effects of MM in bone and osteocyte-derived Scl as a promising target for the treatment of established MM-induced bone disease. Further, Scl did not interfere with efficacy of chemotherapy for MM, suggesting that combined treatment with anti-myeloma drugs and Scl-Ab should effectively control MM growth and bone disease, providing new avenues to effectively control MM and bone disease in patients with active MM.

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Acknowledgements

We thank Kevin McAndrews, Amy Y. Sato and Dan Zhou for assistance in tissue collection. Scl-Ab was provided by Eli Lilly (Indianapolis, IN, USA). Sost−/− mice were provided by Amgen Inc. (Thousand Oaks, CA, USA) and UCB (Brussels, Belgium). This work was supported by the NIH (Indiana-CTSI P30, 1R21CA179017-02 and R01AR059679 to GDR; R01AR059357, R01 DK076007 and S10-RR023710 to TB), the VA (Merit Review to TB and to GDR). JDC received an IBMS Gideon and Sevgi Rodan Fellowship and an ASH Scholar Award.

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Authors and Affiliations

  1. Department of Anatomy and Cell Biology, Indiana University, Indianapolis, IN, USA,

    J Delgado-Calle, M D Cregor, K W Condon, L I Plotkin & T Bellido

  2. Roudebush Veterans Administration Medical Center, Indianapolis, IN, USA

    J Delgado-Calle, L I Plotkin, T Bellido & G D Roodman

  3. Division of Hematology/Oncology, Department of Medicine, Indiana University, Indianapolis, IN, USA

    J Anderson & G D Roodman

  4. Lilly Research Laboratories, Indianapolis, Indiana, USA

    S A Kuhstoss

  5. Division of Endocrinology, Department of Medicine, Indiana University School of Medicine, Indiana University, Indianapolis, IN, USA

    T Bellido

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Correspondence to T Bellido or G D Roodman.

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Competing interests

GDR has received consulting honoraria from Amgen Inc. SAK is an employee of Lilly Research Laboratories. The remaining authors declare no conflict of interest.

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Delgado-Calle, J., Anderson, J., Cregor, M. et al. Genetic deletion of Sost or pharmacological inhibition of sclerostin prevent multiple myeloma-induced bone disease without affecting tumor growth. Leukemia 31, 2686–2694 (2017). https://doi.org/10.1038/leu.2017.152

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